Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12gene.
This gene encodes a member of the cytochrome P450 superfamily of enzymes and is part of a cluster of cytochrome P450 genes on chromosome 19. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein likely localizes to the endoplasmic reticulum. CYP4F12 is expressed in the liver and throughout the gastrointestinal track, is known to metabolize the anti-histamine drugs, ebastine and terfenadine, and therefore is suggested to be positioned for and possibly involved in the processing of these and perhaps other drugs.
When expressed in yeast the enzyme is capable of oxidizing arachidonic acid by adding a hydroxyl residue to carbons 18 or 19 to form 18-hydroxyeicosatetraenoic acid (18-HETE) or 19-HETE; however, its physiological function in doing so has not been determined. CYP4F12 also metabolizes prostaglandin H2 (PGH2) and PGH1 to their corresponding 19-hydroxyl analogs in a reaction that might serve to reduce their activities. In addition to these monooxygenase actions, CYP458 possesses epoxygenase activity: it metabolizes the omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid, (EPA) to their corresponding epoxides, the epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs), respectively. The enzyme metabolizes DHA primarily to 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and EPA primarily to 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ). 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule which acts to onstrict arterioles, elevate blood pressure, promote inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDPs (see Epoxydocosapentaenoic acid) and EEQs (see epoxyeicosatetraenoic acid) have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines. It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, DHA acid and EPA, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally.
The fatty acid metabolizing activity, including the ability to form epoxides, of CYP4F12 is very similar to that of CYP4F8. However, it and CYP4F8 are not regarded as being major contributors in forming the cited epoxides in humans although they might do so in tissues where they are highly expressed.
^ abStark, Katarina; Wongsud, Buanus; Burman, Robert; Oliw, Ernst H. (15 September 2005). "Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8". Archives of Biochemistry and Biophysics441 (2): 174–181. doi:10.1016/j.abb.2005.07.003. ISSN0003-9861. PMID16112640.
^ abFleming I (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID25244930.
^Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH (March 2014). "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research55 (6): 1150–1164. doi:10.1194/jlr.M047357. PMID24634501.
Knight JA, Fronk S, Haymond RE (1975). "Chemical basis and specificity of chemical screening tests for urinary vanilmandelic acid". Clin. Chem.21 (1): 130–3. PMID1116264.
Hashizume T, Imaoka S, Hiroi T, et al. (2001). "cDNA cloning and expression of a novel cytochrome p450 (cyp4f12) from human small intestine". Biochem. Biophys. Res. Commun.280 (4): 1135–41. doi:10.1006/bbrc.2000.4238. PMID11162645.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet.36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Stark K, Wongsud B, Burman R, Oliw EH (2005). "Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8". Arch. Biochem. Biophys.441 (2): 174–81. doi:10.1016/j.abb.2005.07.003. PMID16112640.
Otsuki T, Ota T, Nishikawa T, et al. (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Res.12 (2): 117–26. doi:10.1093/dnares/12.2.117. PMID16303743.